Attention Orange Book Junkies: FDA Petition Response Cements Orange Book Preface Therapeutic Equivalence Clarification

By Kurt R. Karst –      

FDA’s April 2009 response to a September 2007 suitability petition requesting permission to submit an ANDA  for a lyophilized generic version of  ZOMETA (zoledronic acid) Injection and an FDA determination that such drug product, if approved, would be therapeutically equivalent to a ready-to-use solution version of ZOMETA Injection reaffims a recent change in the therapeutic equivalence definition of “AP” rated drug products described in the Orange Book Preface.  That change clarified that lyophilized powders for reconstitution and ready-to-use solutions are pharmaceutical alternatives and are not “AP” rated to one another. 

Pharmaceutically equivalent prescription drug products (i.e., generally drug products in the same strength, route of administration, dosage form, and containing the same active ingredient) are identified in the Orange Book with either an “A” or “B” therapeutic equivalence code designation.  “A-rated” drug products are considered to be to therapeutically equivalent to other pharmaceutically equivalent products, because there are no known or suspected bioequivalence problems, or such problems have been resolved with adequate evidence supporting bioequivalence.  “B-rated” drug products are not considered to be therapeutically equivalent to other pharmaceutically equivalent drug products, because actual or potential bioequivalence problems identified by FDA have not been resolved by adequate bioequivalence evidence. 

Drug products assigned an “A” rating fall under one of two categories: (1) those active ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, and for which bioequivalence to the Reference Listed Drug (“RLD”) is presumed and considered self-evident based on other data in an application or by a showing that an acceptable in vitro dissolution standard is met; or (2) those active ingredients or dosage forms presenting a potential bioequivalence problem, but the applicant’s approved application contains adequate scientific evidence establishing (through in vivo and/or in vitro studies) the bioequivalence of the product to a selected RLD.  Drug products that fall under the first category are assigned a therapeutic equivalence code depending on the dosage form.  These codes include “AA,” “AN,” “AO,” “AP,” or “AT.”  Drug products that fall under the second category are coded “AB” (the most common code assignment).  AP-rated drug products are injectable aqueous solutions and, in certain instances, intravenous non-aqueous solutions.

The 2007 Orange Book Preface stated with respect to AP-rated drug products that:

Injectable products available as dry powders for reconstitution, concentrated sterile solutions for dilution, or sterile solutions ready for injection are all considered to be pharmaceutically and therapeutically equivalent provided they are designed to produce the same concentration prior to injection and are similarly labeled.

That description was changed in the 2008 Orange Book Preface to state:

Injectable products available as dry powders for reconstitution, concentrated sterile solutions for dilution, or sterile solutions ready for injection are pharmaceutical alternative drug products.  They are not rated as therapeutically equivalent (AP) to each other even if these pharmaceutical alternative drug products are designed to produce the same concentration prior to injection and are similarly labeled.

This clarification was made after FDA responded to a July 2006 suitability petition in which the petitioner requested that FDA determine whether a lyophilized formulation of ELOXATIN (oxaliplatin) Injection was withdrawn for safety or effectiveness reasons, permit the submission of an ANDA for a lyophilized generic version of ELOXATIN, and determine that the proposed generic product “would be therapeutically equivalent to the currently marketed [ready-to-use solution] product.”  In its response, FDA stated:

The Eloxatin powder formulation would be considered to be a different dosage form than the Eloxatin aqueous solution because injectable dry powders and injectable solutions are different dosage forms.  Two drug products are rated as therapeutic equivalents in the Orange Book, only if, among other things, they are pharmaceutical equivalents, which is defined, in part, as being of the same dosage form . . . .  An injectable dry powder would be considered a pharmaceutical alternative to an injectable solution . . . .

FDA’s response concerning generic ELOXATIN tracks FDA’s response on the same topic for generic ZOMETA. 

Apparently the AP rating description in the 2007 Orange Book Preface had led some to believe that injectable dry powders and solutions would be AP-rated.  This is understandable, because, until recently, FDA lumped most injectable drug products into a single “Injectable” dosage form descriptor, even though the Agency has historically considered injectable dry powders and solutions to be different dosage forms.